<scp>GPR56</scp> Outperforms <scp>CD319</scp> as a Discriminative Marker for <scp>CD4</scp> ⁺ Cytotoxic T Lymphocytes and Is Elevated in Primary Sjögren's Syndrome

Cytotoxic T lymphocytes (CTLs), especially CD4⁺ CTLs, play a critical role in immune responses against infections and cancers. Nevertheless, the surface markers that define CD4⁺ CTLs remain incompletely characterised, which limits their diagnostic and therapeutic potential. In this study, we investigate CD319 (SLAMF7) and GPR56 as potential surface markers of CD4⁺ CTLs, with a focus on their cytotoxic functions and relevance in primary Sjögren's syndrome (pSS). Using single-cell RNA sequencing and flow cytometry, we detected strong co-expression of GPR56 with cytotoxic effector molecules such as granzyme B in CD4⁺ T cells. Notably, pSS patients showed an elevated frequency of CD4⁺GPR56⁺ T cells, which was associated with disease severity, indicating their potential contribution to pSS pathogenesis. Comparative transcriptomic analysis revealed distinct gene expression profiles between CD4⁺GPR56⁺ and CD4⁺GPR56^- T cells, with enriched pathways related to immune activation and cytotoxicity. Together, our results identify GPR56 as a novel and functionally significant surface marker for CD4⁺ CTLs, providing new insights into their role in autoimmune disorders and their potential for targeted therapeutic strategies.